This invention relates to analgesic drugs and methods of inducing analgesia. More particularly, this invention relates to an analgesic drug containing, as an analgesic component, at least one capsaicinoid and, as a potentiator for the capsaicinoid, dextromethorphan, dextrorphan and/or pharmaceutically acceptable salt thereof.
Capsicum oleoresin, an extract of capsicum (dried red pepper and other species of the genus Capsicum such as Capsicum frutescens and Capsicum annum), contains the capsaicinoid capsaicin (trans-8-methyl-N-vanillyl-6-noneamide). Both capsicum oleoresin and capsicum have for many years been used in a variety of over-the-counter topical analgesic medications such as HEET, INFRA-RUB, OMEGAOIL, and SLOAN's LINIMENT. See also, U.S. Pat. No. 3,880,996 which discloses a topically administered analgesic compositions for the symptomatic relief of localized pain of musculo-skeletal etiology containing, inter alia, capsicum oleoresin.
Cutaneous pain and other sensations of inflammatory pain are thought to be mediated by substance P, an endogenous neuropeptide. Capsaicin enhances the release of substance P from neurons preventing its reaccumulation. As a result of this effect, capsaicin is believed to render skin insensitive to pain by depleting substance P from peripheral sensory neurons. See, Jessell et al., "Capsaicin-induced depletion of substance P from primary sensory neurones", Brain Research, 152 (1978) 183-188.
Combinations of capsaicin and an opioid analgesic such as morphine, codeine, hydromorphone, oxycodone, hydrocodone, oxymorphone, propoxyphene, levorphanol, meperidine, fentanyl, methadone, pentazocine, butorphanol and nalbuphine are disclosed in U.S. Pat. No. 4,599,342, combinations of capsaicin and a nonsteroidal antiinflammatory, antipyretic and analgesic drug such as aspirin, salicylic acid, sodium salicylate, methyl salicylate, diflusinal, phenylbutazone, indomethacin, zomapirac acid, sulindac, fluproquazone, mefenamic acid, ibuprofen, naproxen, ketoprofen, fenoprofen, suprofen, flurbiprofen benoxaprofen, pirprofen, carpoprofen, acetaminophen and phenacetin are disclosed in U.S. Pat. No. 4,681,897 and combinations of capsaicin with the local anesthetic lidocaine or benzocaine are disclosed in U.S. Pat. No. 4,997,843.
Delivery vehicles for topically administered drugs such as capsaicin and capsicum include the gels disclosed in U.S. Pat. Nos. 5,178,879, 5,306,504 and 5,420,197. A non-occlusive adhesive patch for the topical administration of capsicum or other topical medication is disclosed in U.S. Pat. No. 5,536,263 and in commonly assigned copending U.S. patent application Ser. No. 08/675,348, filed Jul. 3, 1996.
Dextromethorphan is a common ingredient of cough, cold and flu medications due to its antitussive (cough-suppressing) activity. Dextromethorphan is widely and authoritatively regarded as lacking analgesic activity, one of several pharmacological properties that distinguishes it from the opiate analgesics of the morphine type to which it is structurally related. Thus, Goodman and Gilman's "The Pharmaceutical Sciences", 17th ed., Mack Pub. (1985), page 870 states that "unlike codeine, [dextromethorphan] is devoid of analgesic properties . . . ", "Drug Evaluation Annual 1998", American Medical Association, 1994, page 469 states that dextromethorphan ". . . does not have additive, analgesic, or sedative actions . . . " and Kirk-Othmer, "Encylopedia of Chemical Technology", 3rd ed., Vol. 9, John Wiley & Sons (1980), page 551, states that "[i]n the case of 3-methoxy-N-methylmorphinan, the levorotatory isomer was found to possess both analgetic and antitussive activity whereas the dextrorotatory isomer (dextromethorphan (37)) possessed only antitussive activity." Unlike the opioid analgesics, dextromethorphan in therapeutic dosages does not produce respiratory depression. Even the antitussive effects of dextromethorphan differ from those of the opioid analgesics; thus, e.g., the antitussive effects of the opioid analgesic codeine are antagonized by naloxone but those of dextromethorphan are not. And, unlike the opioid analgesics, dextromethorphan poses so little risk of abuse that it is specifically stated to be a non-scheduled drug (21 U.S.C. .sctn.811(g)(2)).
The few known exceptions to dextromethorphan's lack of analgesic activity involve specific pain conditions, e.g., mouth pain as disclosed in U.S. Pat. No. 4,446,140, dysmenorrhea (vaginal cramps) as disclosed in EPA 81,823 and chronic pain as disclosed in U.S. Pat. No. 5,352,683. More recently it has been disclosed in PCT publication WP 96/07412 that while dextromethorphan does not have general analgesic usefulness when administered alone, it significantly enhances, or potentiates, the analgesic activity of a nonsteroidal antiinflammatory drug (NSAID) or acetaminophen with which it is administered for all types of pain.